Solid state ophthalmic medication delivery method

ABSTRACT

1. IN THE METHOD OF OBTAINING THE OPHTHALMIC PHARMACOLOGICAL EFFECT OF A MEDICAMENT COMPRISING INSERTING A COMPLETE OPHTHALMIC DISAGE OF MEDICAMENT IN SOLID FORM INTO THE CUL-DE-SAC OF THE EYE BETWEEN THE EYEBALL AND THE LID TO DISPENSE THE MEDICAMENT TO THE EYE OVER A PROLONGED PERIOD OF TIME, THE IMPROVEMENT BY MEANS OF WHICH THE CUL-DE-SAC IS LEFT FREE OF TEAR INSOLUBLE RESIDUE AFTER SAID MEDICAMENT IS DISPENSED, WHICH COMPRISES EMPLOYING A SOLID MATRIX OF A NON-IRRITATING PHARMACOLOGICALLY ACCEPTABLE POLYURONIC ACID OR CARBOXYMETHYLCELLULOSE SALT OF SAID MEDICAMENT, FREE FROM TEAR INSOLUBLE CARRIERS, SAID MATRIX ADAPTED TO FORM A GEL-MATRIX AFTER INSERTION INTO THE CULDE-SAC AND TO DISSOLVE COMPLETELY FOR SLOW RELEASE OF SAID DOSAGE.

Oct.. 29. 1974 H. M. HADDAD ETAL l SOLID ySTATE OPHTHLMIC MEDICATIONDELIVERY METHD Filed Apri124, '1972 3 Sheets-Sheet 'L M. N O

0121329, 1974 H M, HADDAD ETAL.

SOLID STATE OPHTHALMIC MEDICATION DELIVERY METHOD Filed April 24. 1972If Sheets-Sheet 2 `SOLID STATE OFHTHALMIC MEDICATION DELIVERY METHODFiled April 24, 1972 oct. 29, 1974 H M HADDAD ETAL 3 Sheets-Sheet 5United States 'Patent O 3,845,201 SOLID STATE OPHTHALMIC MEDICATIONDELIVERY METHOD Heskel M. Haddad, 1200 5th Ave., New York, N.Y.

10029, and Spiro P. Loucas, 16 Toni Court, Plainview,

Filed Apr. 24, 1972, Ser. No. 246,661 Int. Cl. A61k 27/12 U.S. Cl.424-22 16 Claims ABSTRACT OF THE DISCLOSURE A method of delivering amedicament to the eye in solid form is described. The duration ofmiotic, mydriatic or other pharmacological activity is prolonged by thedirect insertion of solid dosage forms of pharmacologically activecompounds in the cul-de-sac of the conjunctiva.

BACKGROUND OF THE INVENTION This invention relates to a method ofdispensing drugs to the eye over a prolonged period of time.

At the present time, drugs of various kinds are frequently employed inophthalmic practice for the treatment of eye diseases. Since these drugsare rapidly excreted from the body or diffuse from any site of localapplication, repeated or numerous administration of the drug during thecrucial period is generally necessary. Therapeutic substances may beintroduced into the eye by 'various methods. The methods generally usedare instillation in the conjunctival sac, subconjunctival injection,iontophoresis, systemic administration and direct injection into theglobe itself. The most common route is by instillation into theconjunctival sac in the form of drops or ointments. In this method,drugs enter the eye largely through the cornea but to be eiective, inmany cases, the application of the drug must be substantiallycontinuous. At the present time, it is not possible to o'btaincontinuous delivery of a given drug through the use of drops orointments even though they are applied at intervals during a givenperiod. Periodic application of such dosage forms generally results inthe eye receiving a large but uncertain amount of the drug at the momentit is applied, but the drug is washed away rapidly by tears, thusleaving the eye without medication until the next application. Forexample, persons suffering from glaucoma, a symptomatic conditioncharacterized by an increase in intra-ocular pressure, must use eyedropsin large quantities and at frequent intervals in order to maintain thebase pressure below a reasonable level. Pilocarpine is generally used inthe treatment of glaucoma, but frequent administration is required dueto the fact that the hypotensive action of the drug is not of longduration. Thus, there still remains a need to find better methods ofdelivering drugs to the eye so as to obtain the maximum effect from thedrug without the need for frequent administration.

One method which has been proposed for the treatment of acute glaucoma,for example, is to deliver the drug to the eye enclosed in a polyvinylmembrane. This method was proposed by Vropaeva & Indeikin in Oftal. Zh.,24: 543 (No. 7) 1969. The membrane containing the drug is applied totheeyelid. However, it was found that the inclusion of the drug in amembrane did not increase the effectiveness of the drug in the generaltreatment of acute attacks of glaucoma. An additional drawback is theneed to remove the membrane which contains the drug from the eye aftereach application.

U.S. Pat. No. 3,618,604 describes an ocular insert which is used todispense drugs to the eye. The insert is comprised of a polymericmaterial which is insoluble in tear liquid, the body of which containsthe drug. The drug 3,845,201 Patented Oct. 29, 1974 ice is thendispensed to the eye 'by ditfusion through the polymeric material. Thismethod has an inherent disadvantage in that the insert must be removedfrom the eye each time after app-lication of the drug. In addition, thepolymeric insert must be so fashioned that it will not irritate thesensitive tissues of the eye.

U.S. Pat. No. 3,630,200 describes an ocular insert made up of an innercore having an ainity for a given drug and a soft hydrophilic outerlayer. U.S. Pat. No. 3,626,940 also describes an ocular insertfabricated from polymeric materials, but the insert contains amagnetically attractable substance to permit insertion and removal ofthe insert by magnetic means. Thus, each of the drug dispensing methodsdescribed in the above patents requires removal of the insert after eachapplication of the drug.

Other methods include the use of vehicles such as methylcellulose in thepreparation of ophthalmic solutions because of the apparent ability ofthis compound to prolong the action of medicaments which have beendissolved in such solutions. Although the use of methylcellulosesolutions prolongs the actions of the medicament, frequent applicationof eyedrops made from such solutions is still required in order to bringa suiicient quantity of the drug in contact with the eye. Other agentshave been added to ophthalmic solutions for the purpose of prolongingthe eifect of the drug, but each of these methods requires the use ofsolutions which must be placed in the eye at frequent intervals.

The object of the present invention is to provide a method of deliveringa therapeutic drug to the eye in solid form which results in acontinuous controlled release of the medicament and o'bviates the needfor frequent administration of the drug.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relatesto a method of treating diseases of the eye which comprises delivering amedicament in solid form to the eye. The drug, in the form of a disc,pellet, flake, wafer, etc. is placed in the cul-de-sac of theconjunctiva between the eyeball and the eyelid. While the disc can beinserted under either the upper lid or the lower lid, it is preferred toplace the disc under the lower lid. Once the disc is in place, the drugdisintegrates slowly causing it to be released into the tear tiuids. Thedrug is transported to the eyeball by the flow of tear tiuid or by theblinking action of the eyelids. A slow diffusional process controls therate of loss of the drug from its solid matrix; thus, the drug is heldin reserve and is available for prolonging the duration of a desiredpupillary response. Due to the slow diiusional process, a means is thusprovided for controlling the release of a given drug from its dosageform in which availability for absorption from the cul-de-sac is moreuniform than is the case with ophthalmic solutions containing the drugs.Thus, a single disc can provide the complete ophthalmic dosagerequirement for a particular time period depending upon theconcentration of the drug in a given disc. Moreover, frequent repeatedapplications of the drug are unnecessary, which is not the case withsolutions and ointments. For the purpose of lessening any irritationwhich may result from the initial contact of the solid with the eye, thesolid may be dipped in an isotonic solution which causes the solid toassume a semi-plastic consistency. Generally, physiological saltsolutions are suitable 'for this purpose.

Any drug normally used to treat diseases of the eye and the surroundingtissues can be employed which is a solid or can be made into a solidderivative. Also, within the contemplation of the present invention isthe use of drugs which will pass through the eye or the tissue sur- 3rounding the eye into the bloodstream, but which may not be used intreatment of the eye itself.

Some examples of drugs used in ophthalmic therapy which may be employedin the present invention are: anti-infectives: such as antibiotics,including tetracycline, chlortetracycline, bacitracin, neomycin,polymyxin, gramicidin, oxytetracycline, chloramphenicol, anderthromycin; sulfonamides, including sulfacetamide, sulfamethizole, andsulsoxazole; antivirals, including idoxuridine; and otheranti-infectives including nitrofurazone and sodium propionate;antiallergenics such as antazoline, methapyrilene, chlorpheniramine,pyrilamine and prophenpyridamine; anti-infiammatories such ashydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone21-phosphate, tiuocinolone, medrysone, prednisolone, prednisolone2l-phosphate and prednisolone acetate; decongcstants such asphenylephrine, naphazoline, and tetrahydrazoline; miotics andanticholinesterases such as pilocarpine, eserine salicylate, carbachol,diisopropyl fluorophosphate, phospholine iodide, and demaearium bromide;mydriatics such as atropine sulfate, cyclopentolate, homatropine,scopolamine, tropicamide, eucatropine, and hydroxyamphetamine andsypathornimetics such as epinephrine. The drugs can be in various formssuch as uncharged molecules, components of molecular complexes, ornonirritating, pharmacologically acceptable salts, such as thehydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate,acetate, maleate, tartrate, salicylate, salts of polyuronic acids suchas alginic acid, galactouronic acid and glucouronic acid, and saltsprepared from carboxymethylcellulose. Furthermore, simple derivatives ofthe drugs such as ethers, esters, amides, etc., which have desirableretention and release characteristics but which are easily hydrolyzed bybody pH, enzymes, etc. can be employed. The amount of drug used to makeup the solid dosage form will vary Widely depending upon the particulardrug, the desired therapeutic etfect, and the time span for which thesolid dosage form will be used. There is no critical upper limit on theamount of the drug used since the solid dosage is intended to providethe complete dosage requirement for a given period. The lower limit willdepend on the activity of a given drug and its rate of diffusion in thetear fluids. Therefore, it is not practical to define a particular rangefor a therapeutically effective amount to be used to make up the soliddosage. However, generally about 1-50 mg. will be employed in the usualsolid form, depending upon the particular drug employed. The preferredrange is from about 1-10 mg.

The solid dosage form can be prepared by any conventional method used toprepare discs, pellets, wafers, etc. from solids. One method, forexample, involves dissolving the medicament in a solvent such as water,placing the solution in a suitable container or vessel and removing thesolvent by evaporation. Where desired, the semisolid mass left uponpartial evaporation can be sectioned into the desired shape by means ofvarious size cutting tools. The solid is then dried to ensure theremoval of all of the solvent. In this manner, it is possible to varythe dimensions of a respective dose by simple replacing the size of thecutting tool or changing the volume of the liquid used in preparation ofthe disc. The disc can be fabricated in any convenient shape, keeping inmind that it must be comfortably retained in the cul-de-sac of the eye.The shape, however, must not have sharp, jagged or rough edges Which mayirritate the sensitive tissues of the eye. The actual shape usedpresents little problem to eye tissue since the initial form is changedupon coming into contact with the eye uids. The solid form of the drugmay be a disc, pellet, iiake, etc.; it can be concave, convex,rectangular, etc. The original shape of the solid drug form is not ofcritical importance. The actual size of the solid dosage form will varywidely. The lower limit will be governed by the amount of the particulardrug to be applied to the eye to obtain the desired opthalmic response.The upper limit will be governed by the smallest sized solid which canbe conveniently inserted into the cul-de-sac. Generally, the solid formwill be about 1-8 mm. in length, about 1-4 mm. in width, having athickness of about 0.2-1 mm. The preferred shape is a disc having athickness of about 0.3 mm., a diameter of 3-7 mm., and a weight of about3.0-8 mg.

Although the duration of the pharmacological etfect of the drug in theeye will depend upon the particular drug employed and the amount used,solid form delivery of the drug generally results in a pupillaryresponse of up to 7-8 hours in the animal and longer in humans.

Those compounds which are normally solids may be delivered in the formof a disc or pellet, etc. without the aid of an additive. Thosecompounds which are normally liquid may be used in the form of apharmacologically acceptable solid derivative. Also contemplated is theuse of a diluent or vehicle in conjunction with the solid dosage form.Suitable vehicles include, for example, methylcellulose,hydroxypropylmethylcellulose, diethylaminoethylcellulose,polyvinylpyrrolidone and pharmacologically acceptable cationic oranionic resins.

The treatment of eye diseases by delivering the medicament directly tothe cul-de-sac of the eye in solid form has general application tovarious diseases of the eye. Any condition where prolonged drugadministration is required may be treated in this manner. For example,it is possible to treat in this manner such eye disorders as uveitis,glaucoma, diseases of the cornea such as, for example, purulentkeratitis, herpes simplex keratitis, herpes zoster, acne rosacea,interstitial keratitis, and the like, diseases of the orbit such asexophthalmas and periostitis and diseases of the conjunctiva such asmucopurulent conjunctivitis and ophthalmia. The present mode of drugdelivery may also be used when postoperative treatment is required suchas after retinal and cataract surgery.

An additional disadvantage related to the use of solutions of drugs inthe treatment of diseases of the eye is the instability of most drugs insolution. Drug solutions generally contain a preservative to preventbacterial growth. The pH of eye fluids is about 7.4 while the pH ofcommercial pilocarpine solutions is about 5.3-5.5. It is known thatacidic solutions tend to cause discomfort to the eye. The administrationof the drug in solid form, however, circumvents the problems relating tostability and eye discomfort since the drug in solid form is stable foran indefinite period.

In a specific example of the method of delivering a drug to thecul-de-sac in solid form, in accordance with the present invention,pilocarpine is prepared in the form of a disc and used to treat thesymptoms of glaucoma. Glaucoma is a clincial condition which ischaracterized by an increase in intra-ocular pressure. The tension whichis associated with chronic simple glaucoma requires careful study andrepeated observation. In cases of chronic simple glaucoma, miotictreatment is -generally instituted. The most commonly used miotic ispilocarpine which is administered several times a day. A solution ofabout 0.5-4% is used in early cases, but stronger solutions are usedwhen necessary to control the condition. Eserine can be used generallyin an 0.025-l.0% solution if necessary and, in certain instances,stronger chloinergic drugs such as echothiophate iodide (phospholineiodide) may be employed.

In treating glaucoma, pilocarpine is generally administered in the formof an aqueous solution, but it may also be administered in the form ofan ointment or by injecttion. The eye drops commonly used to make up thesolution generally consist of an aqueous solution of pilocarpinehydrochloride. The present inventors have found that delivery of thedrug, pilocarpine in the present example, to the cul-de-sac of the eyein the form of a solid disc provides a means for controlling the releaseof the drug from a given dosage form. The availability of the drug forabsorption from the cul-de-sac is more uniform than that obtained frominorganic salt type opthalmic solutions.

The effectiveness of the administration of the drug in solid form isillustrated by the following example. The acid salts used in the exampleare prepared by conventional methods used to prepare acid addition saltsfrom compounds containing a base nitrogen.

EXAMPLE 1 A. Preparation of ophthalmic solid dosage forms (a)Pilocarpine alginate-ophthalmic discs are prepared by dissolvingpilocarpine alginate powder (7% w./v.) in a small quantity of sterilewater with stirring. The solution is placed in a at-bottom petri dishand evaporated under reduced presure at 30 C. in a thermostatic waterbath assembly. When the colloidal solution reaches a semi-solidconsistency, the mass is sectioned into circular flakes (0.3 mm.thickness, 3-7 mm. diameter, 3.17.8 mg.) by means of various sizetrephines and the sections are dried to the point of solidification at30 C. The solid is dried for an additional 24 hours at room temperatureand the discs are removed and stored in lightresistant containers.

(b) Pilocarpine hydrochloride-A disc was prepared in the same manner asin a) above using 14.7 mg. of pilocarpine hydrochloride and 100 mg. ofmethylcellulose 4000 cps. in sterile water for injection. A discweighing 4.6 mg. was obtained.

(c) Pilocarpine alginate- A disc was prepared in the same manner as ina) above using 22 mg. of pilocarpine alginate and 0.23 mg. ofmethylcellulose in sterile free water for injection. A disc weighing22.23 mg. was obtained.

(d) Pilocarpine-A disc was prepared as in a) above using 4 mg. ofpilocarpine. A disc weighing 4 mg. was obtained.

B. Preparation of ophthalmic solutions (a) Pilocarpine alginate (3.34%W./v.) solution was prepared from sterile Sorensen phosphate bufferstock solutions mixed in varying proportions to give a final pH of 6.14.The solution was adjusted for toxicity with sodium chloride.

(b) Pilocarpine hydrochloride solution (2.00% w./v.) in the presence ofmethylcellulose 4000 cps. required to adjust the viscosity to that ofthe alginate in a) above (72 cps., Brookfield viscosimeter, model LVT,25 C.) was prepared from sterile Sorensen phosphate buffer stocksolutions mixed in varying proportions to give a .final pH of 6.14 andadjusted for toxicity with sodium chloride.

PREPARATION A 1. Pilocarpine alginate-Pilocarpine free base (5 g.) andalginic acid powder (5 g.) are mixed together in 50 ml. of sterile,distilled Water with stirring. The mixture is heated in a water bath at50 C. and the stirring is continued for 1 hour. The resulting gel iscooled to room temperature and the stirring is continued for 24 hoursunder reduced light. The mixture is then diluted to 100 ml. withdistilled water and the resulting solution is stirred for l2 hours atroom temperature. The solution is then transferred to a dessicator-waterbath assembly and evaporated to dryness under reduced pressure at 30 C.The dry powder left upon removal of the water is used directly toprepare the disc and the solution of pilocarpine alginate.

Albino male rabbits are allowed to equilibrate under constant conditionsof illumination for twenty-four hours prior to treatment with liquid andsolid dosages of pilocarpine.

Each solution is delivered from a micrometer syringe (0.075 ml.) intothe lower cul-de-sac of one eye. Aqueous alginic acid or aqueoushydrochloric acid is placed in the other eye as a control. The disc issoaked in isotonic sodium chloride solution and then deposited into thelower cul-de-sac with the aid of forceps. 'Ihe alginic acid andmethylcellulose disc is used as a control. The size of each pupil ismeasured just before the test drug is applied by means of an OptikerRyer pupillary gauge fixed at a distance of six inches from the globe.During measurement, the animals are confined in a Wooden box whichprovides free head and neck motion. Prior to taking measurements, awaiting period of one minute is exercised from the time the gauge isbrought within the above distance. At specified time intervals, at leastsix pupillary diameter readings are made at each point.

Pupillary responses indicate (FIG. l) that, in the liquid state,pilocarpine alginate exhibits essentially comparable miotic activity aspilocarpine hydrochloride following single dose treatment. No pupillarycontraction is noted in both liquid and solid dose control eyes. Theresults derived from solid pilocarpine alginate deposition show themagnitude of maximum pupil size constriction to be enhanced, withduration of miosis significantly increased over that of both liquiddosage systems. Restoration of normal pupillary diameter for the solidstate dose is observed to occur between 7 and 8 hours in contrast to3-3V2 hours for the ophthalmic solutions.

In FIG. 2, data for repetitive pilocarpine alginate disc application aregiven. In this study phase, miotic activity is monitored after repeatingthe dose at maximum pupil constriction, 50% and 100% recovery ofpupillary diameter. Repeating the treatment at 50% pupil recovery givesabout a two-fold increase in miotic duration relative to both singledose deposition and normal pupillary diameter and multiple treatments atthe points of maximum constriction. When a second and third disc isapplied at recovery (7 mm.), the behavior is additive with restorationof pupil size being reached after seven, twelve and about seventeenhours.

Overall duration of miosis in the case of triplicate liquid treatments(FIG. 3) at recovery shows that activity derived from solutions ofpilocarpine alginate and pilocarpine hydrochloride methylcellulose isessentially equal. Recovery from the first, second and third dropinstillations is reached at about four, seven and ten hours,respectively.

The availability of the medicament in the cul-de-sac from solid formdoses appears to be more uniform as a consequence of diminisheddiffusion through the gel matrix where the drug is held in reserve incontrast to liquid dosage forms when the dose is immediately released inthe conjunctional uids. Although the rate of diffusion of the solid drugwill depend on the given drug employed, the concentration of a givendisc can be controlled so as to allow maximum dosage over a given periodonce the rate of diffusion of a given drug is known. The use of solidophthalmic dosages in the treatment of diseases of the eye is moreeffective than conventional methods and requires less frequentadministration of the drug to produce prolonged physiological activity.

While a preferred embodiment of the present invention has beendescribed, it is apparent that numerous variations and additions may bemade to the invention without departing from the spirit thereof. It isthe intention, therefore, to be limited only by the scope of thefollowing claims:

What is claimed is:

1. In the method of obtaining the ophthalmic pharmacological effect of amedicament comprising inserting a complete ophthalmic dosage ofmedicament in solid form into the cul-de-sac of the eye between theeyeball and the lid to dispense the medicament to the eye over aprolonged period of time, the improvement by means of which thecul-de-sac is left free of tear insoluble residue after said medicamentis dispensed, which comprises employing a solid matrix of anon-irritating pharmacologically acceptable polyuronic acid orcarboxymethylcellulose salt of said medicament, free from tear insolublecarriers, said matrix adapted to form a gel-matrix after insertion intothe culde-sac and to dissolve completely for slow release of saiddosage.

2. The method of claim 1 wherein the medicament is employed in the formof a disc capable of assuming essentially the conguration of thecurvature between the eyeball and the lid.

3. The method of claim 1 wherein the medicament employed is in the formof a salt of a polyuronic acid.

4. The method of claim 3 wherein the polyuronic acid is alginic acid.

5. The method of claim 1 wherein the medicament is a miotic.

6. The method of claim 5 wherein the miotic is selected from the groupconsisting of pilocarpine, eserine and carbachol.

7. The method of claim 1 wherein a vehicle is additionally present, saidvehicle being selected from methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose,diethylaminoethylcellulose, polyvinylpyrrolidone and pharmacologicallyacceptable cationic and aniom'c resins.

8. The method of obtaining the ophthalmic pharmacological effect of amedicament for treating glaucoma eomprising inserting a completeophthalmic dosage of medicament in solid form into the cul-de-sac of theeye between the eyeball and the lid to dispense the medicament to theeye over a prolonged period of time, the improvement by means of whichthe cul-de-sac is left free of tear insoluble residue after saidmedicament is dispensed, which comprises employing a solid matrix of anon-irritating pharmacologically acceptable polyuronic acid orcarboxymethylcellulose salt of said medicament, free from tear insolublecarriers, said matrix adapted to form a gel-matrix after insertion intothe cul-de-sac and to dissolve completely for slow release of saiddosage.

9. The method of claim 8 wherein the medicament is employed in the formof a disc capable of assuming essentially the configuration of thecurvature between the eyeball and the lid.

10. The method of claim 9 wherein the medicament is in the form of adisc having a thickness of about .3 mm., a diameter of about 3-7 mm.,and a weight of about 3-8 mg.

11. The method of claim 9 wherein the medicament is present in the formof a salt of a polyuronic acid.

12. The method of claim 9 wherein the polyuronic acid is selected fromthe group consisting of alginic acid, galactouronic acid and glucouronicacid.

13. The method of claim 8 wherein the medicament is selected from thegroup consisting of Pilocarpine, eserine, carbachol andpharmacologically acceptable salts thereof.

14. The method of claim 12 wherein the pharmacologically acceptable saltis pilocarpine alginate.

15. The method of claim 8 wherein a vehicle is additionally present,said vehicle being selected from the group consisting ofmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose,diethylaminoethylcellulose,

polyvinylpyrrolidone, and pharmacologically acceptable cationic andanionic resins.

16. In the method of obtaining the ophthalmic pharmacological elect of amedicament which comprises insertion of a complete ophthalmic dosagerequirement, said medicament being in solid disc, pellet or wafer form,for inserting into the cul-de-sac of the eye between the eyeball and thelid, to dispense the medicament to the eye over a prolonged period oftime, the improvement which comprises a complete ophthalmic dosagerequirement of said medicament formulated as a non-irritatingpharmacologically acceptable polyuronic acid or carboxymethylcellulosesalt gel-matrix with slow diffusional drug release and availability forabsorption from the cul-de-sac, said salt form of a complete ophthalmicdosage requirement of said medicament being tear-Huid diffusible insolid form, without the aid of an additive, diluent or vehicle, andfurther being free from any solid carrier insoluble in tear fluid andfree from the drawback of the need of removal of any solid carrierinsoluble in tear uid after each application, said solid completeophthalmic dosage being adapted for deposition into the culdesac of theeye after assuming a semi-plastic consistency upon being presoaked inisotonic sodium chloride solution and being adapted to be completelycontrollably released after insertion.

References Cited UNITED STATES PATENTS 3,450,814 6/1969 Bechtold et al.424-180 3,640,741 2/1972 Etes 10'6-170 3,075,527 1/1963 Bechtold 128-260273,410 3/1883 \adleigh 12S-260 3,618,604 11/1971 Ness 128-260 OTHERREFERENCES Iakovlev et al. Vistn. O-ftal 79:40-42 November-December1966, The Use of Pilocarpine in a Polyvinyl Alcohol Film for theTreatment of Glaucomatous Patients.

Maichuk Antibiotiki 12(5):432-435 (1967), Polyvinyl Alcohol Films withAntibiotics in the Therapy of Eye Infections.

Krishna et al., Am. J. Ophthal. 57:99-106 (1964), Polyvinyl Alcohol asan Ophthalmic Vehicle.

Anderson et al., Am. J. Ophthal. 51:1200-1203 (1961), Tissue Response toPolyvinyl Alcohol Implants in Rabbits.

Haas et al., Am. J. Ophthal. 54:21-23 (1962), Ther Eifect ofMethyl-Cellulose on Responses to Solutions of Pilocarpine.

SHEP K. ROSE, Primary Examiner U.S. C1. XR.

1. IN THE METHOD OF OBTAINING THE OPHTHALMIC PHARMACOLOGICAL EFFECT OF AMEDICAMENT COMPRISING INSERTING A COMPLETE OPHTHALMIC DISAGE OFMEDICAMENT IN SOLID FORM INTO THE CUL-DE-SAC OF THE EYE BETWEEN THEEYEBALL AND THE LID TO DISPENSE THE MEDICAMENT TO THE EYE OVER APROLONGED PERIOD OF TIME, THE IMPROVEMENT BY MEANS OF WHICH THECUL-DE-SAC IS LEFT FREE OF TEAR INSOLUBLE RESIDUE AFTER SAID MEDICAMENTIS DISPENSED, WHICH COMPRISES EMPLOYING A SOLID MATRIX OF ANON-IRRITATING PHARMACOLOGICALLY ACCEPTABLE POLYURONIC ACID ORCARBOXYMETHYLCELLULOSE SALT OF SAID MEDICAMENT, FREE FROM TEAR INSOLUBLECARRIERS, SAID MATRIX ADAPTED TO FORM A GEL-MATRIX AFTER INSERTION INTOTHE CULDE-SAC AND TO DISSOLVE COMPLETELY FOR SLOW RELEASE OF SAIDDOSAGE.